Many polyhydroxylated piperidines and pyrrolidines are powerful inhibitors of glycohydrolases, enzymes responsible for glycoprotein processing and the gastrointestinal breakdown of dietary carbohydrates. See, for example, Fleet, G. W. J. Chem. Brit., 1989, 287; Fellows, L. E. Chem. Brit., 1987, 842. These azasugars have potential therapeutic utility in the treatment of various diseases, such as diabetes, cancer and viral infections. Particular attention has focused on anti-HIV activity in the AIDS area. Therefore, the syntheses of polyhydroxylated piperidines and pyrrolidines such as 1-deoxynojirimycin, an antiviral agent, has been the subject of considerable recent research. Bayer, for example, is developing miglitol, a polyhydroxylated piperidine, which is useful as an anti-diabetic agent, Drugs Fut. 1986, 11, 1039.
Synthetic routes to azasugars have commonly entailed processes such as azide displacement/reduction and N-alkylative cyclization with extensive protecting-group manipulation. See, for example, (a) Paulsen, H,; Sangster, I.; Heyns, K. Chem. Ber, 1967, 100, 802. (b) Inouye, S. et al. Tetrahedron 1968, 23, 2125. (c) Saeki, H.; Ohki, E. Chem. Pharm. Bull. 1968, 11, 2477. (d) Kinast, G.; Schedel, M. Angew. Chem. Int. Ed. Engl. 1981, 20, 805. U.S. Pat. No. 4,266,025; May 1981. (e) Vasella, A.; Voeffray, R. Helv. Chim. Acta 1982, 65, 1134 (f) Koebernick, W.; E. P. 55-431; U.S. Pat. No. 4,611,058; Sep. 9, 1986; assigned to Bayer AG. (g) Bernotas, R.; Ganem, B. Tetrahedron Lett. 1985, 26, 1123. (h) Setoi, H.; Takeno, H.; Hashimoto, M. Chem. Pharm. Bull. 1986, 34, 2642. (i) Broxterman, H. J. G. et al. Rec. Trav. Chim. Pays-Bas 1987, 106, 571. (j) Fleet, G. W. J.; Fellows, L. E.; Smith, P. W. Tetrahedron 1987, 43, 979. (k) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337. (1) Ziegler, T.; Straub, A.; Effenberger, F. Angew; Chem. Int. Ed. Engl. 1988, 27, 716. (m) Schmidt, R. R.; Michel, J.; Rucker, E. Liebigs Ann. Chem. 1989, 423. (n) Chida, N.; Furuno, Y.; Ogawa, S. J. Chem. Soc., Chem. Commun. 1989, 1230. (o) Beaupere, D.; Stasik, B. et al. Carbohydr. Res. 1989, 191, 163. (p) von der Osten, C. H. et al. J. Am. Chem. Soc. 1989, 111, 3924. (q) Ikota, N. Heterocycles 1989, 22, 1469. (r) Tsuda, Y.; Okuno, Y.; Iwaki, M.; Kanemitsu, K. Chem. Pharm Bull 1989, 37, 2673. (s) Fleet, G. W. J. et al. Tetrahedron Lett. 1990, 31, 490. (t) Anzeveno, P. B., Creemer, L. J. Tetrahedron Lett. 1990, 31, 2085 (u) Dax, K. et al. J. Carbohydr. Chem. 1990, 9 479. Certain of the semi-synthetic methods employing a key enzymatic transformation have proved to be useful.
U. S. Patent No. 4,611,058 describes high stereo-selectivity in the intramolecular reductive amination of 6-amino-6-deoxy-L-sorbose when using a borohydride reducing agent. U. S. Pat. Nos. 4,806,650 and 4,266,025 describe additional Bayer processes involving the production of 1-deoxynojirimycin. The first patent describes the microbial oxidation portion of the process together with the intramolecular reductive amination. The second patent describes the overall process containing the catalytic reduction of the imine with a palladium on carbon catalyst. The processes for the production of 1-deoxynojirimycin are expensive to run because of the number of chemical steps involved and/or the need for purification of the intermediates or targets. Many of the known processes involve a cyclization step that is not stereoselective resulting in the need for tedious separations.
Piperidines and pyrrolidines have been prepared by double reductive amination of dicarbonyl compounds with an amine and NACNBH.sub.3 (Borch, R. F. et al. J. Am. Chem. Soc. 1971, 22, 2897), but this reaction has not been applied to the preparation of aminosugars from dicarbonyl sugar starting materials.
The present invention involves a synthesis process for amino sugars that is efficient and economic. In particular, the process described is more concise and stereospecific in comparison with the processes for some of the preparations of amino sugars known in the prior art.